CROSS-REFERENCE TO RELATED APPLICATIONS
FIELD OF THE APPLICATION
[0002] The present application relates to new processes and intermediates useful in the
preparation of morphine analogs, such as naltrexone, naloxone and nalbuphine. In a
particular example, the process begins with oxymorphone or oxycodone N-oxides and
includes the formation of an oxazolidine intermediate using a cyclodehydration reagent.
BACKGROUND OF THE APPLICATION
[0003] Various morphine antagonists such as naltrexone, naloxone, and nalbuphine are available
by semi-synthesis from the natural opiates such as morphine, codeine, thebaine or
oripavine, Scheme 1. These compounds are used extensively in medicine as antagonists
(naltrexone and naloxone) and mixed agonist/antagonist (nalbuphine). Naltrexone has
long been used for the treatment of alcoholism, and is the active ingredient in Vivitrol®,
an extended release injectable suspension for the treatment of alcoholism and opioid
dependence. Naloxone is the active ingredient in Narcan® for the reversal of opioid
overdose and is used to mitigate side effects in combination with buprenorphine (Suboxone®)
for the treatment of opioid addiction, with tilidine (Valoron N®) for the treatment
of pain and with oxycodone (Targin®) for the prophylaxis and/or treatment of opioid-induced
bowel dysfunction during the treatment of pain. Nalbuphine is the active ingredient
in Nubain® and is used for the treatment of pain in very low doses particularly in
women.

[0004] The introduction of the C-14 hydroxyl into various natural morphinans to produce
oxycodone and oxymorphone has been reduced to practice on large scales with a high
degree of efficiency by oxidation of thebaine or oripavine. Methods for direct C-H
oxidation at C-14 for compounds such as codeine, morphine, or hydrocodone have been
reported but are not very efficient or practical at this time. On the other hand,
N-demethylation of natural opiates still represents a challenge, especially in terms
of efficiency or the focus on environmentally benign procedures and reagents. Many
methods have been employed for the demethylation; these include the use of cyanogen
bromide (von Braun reaction),
i methyl or ethyl chloroformate,
ii 1-chloroethyl chloroformate (ACE-Cl),
iii and microbial protocols,
iv including a recently published procedure employing fungal biotransformations.
v The biotransformations of several morphine alkaloids with the strain
Cunninghamella echinulata and several others produced the free amines in reasonable yields and purity. Such
processes, when scaled up and improved by the creation of a transgenic vector that
would express the required fungal cytochrome in an
E. coli carrier would have great potential as an environmentally benign N-demethylation protocol.
[0005] Recently, iron (II) as well as iron (0) catalyzed N-demethylation of several morphinan
N-oxides was reported by Scammells.
vi Smith et al.
vii developed a method to convert N-methylated 6-oxo-14-hydroxymorphinanes to the corresponding
nor compounds by treating the corresponding N-oxide with a Fe(II) based reducing agent
in the presence of formic acid to form an oxazolidine. The oxazolidine can be converted
to the corresponding nor-morphinane by acid hydrolysis, as shown in Scheme 2. Conversion
of the
N-oxide to the corresponding oxazolidine works equally well whether the 7,8 carbon
bond is unsaturated or saturated, as shown with oxymorphone, Scheme 2.

[0006] The reactivity of the Burgess reagent, long associated only with the dehydration
of alcohols, has been tested in a variety of ways with other functional groups. The
synthesis of cis-fused sulfamidates was accomplished by the reaction of the Burgess
reagent with epoxides
viii and 1,2-diols;
ix and the Burgess reagent was shown to oxidize thiols to disulfides in high yields.
x New applications
xi as well as more thermally stable forms of this reagent
xii are being reported, including its chiral auxiliary version,
xiii and the reagent has been used extensively in natural product syntheses.
xiv
SUMMARY OF THE APPLICATION
[0007] Because the conversion of natural opiates to their C-14 hydroxy derivatives is well
established, it would be convenient to provide a direct conversion of oxymorphone
to the corresponding analogs via N-demethylation and alkylation. The present application
reports a rather unexpected reaction of a cyclodehydration reagent, such as Burgess
reagent, with N-oxides derived from, for example, oxymorphone and oxycodone to provide
the corresponding oxazolidine, and an efficient conversion of these oxazolidines to
naltrexone, nalbuphine, naloxone, and other analogs.
[0008] Accordingly, the present application includes a process for the preparation of a
compound of Formula I:

comprising:
- (a) reacting a compound of Formula II with an oxidizing agent under conditions to
provide a compound of Formula III:

and
- (b) reacting the compound of Formula III with a cyclodehydration reagent under conditions
to provide the compound of Formula I,
wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present; and
PG is a protecting group; and
wherein in the compounds of Formulae I, II and III, one or more available hydrogens
in R1 and R2 is/are optionally replaced with F and/or one or more of available atoms in R1 and R2 is/are optionally replaced with an isotopic label.
[0009] The compounds of Formula I are useful for the preparation of several different classes
of morphine analogs.
[0010] For example, in one embodiment, the present application also includes a process for
preparing compounds of Formula V:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present;
PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl; and
X is a counteranion, comprising
reacting a compound of Formula I:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present; and
PG is a protecting group,
with an alkylating reagent of Formula VI:
R3-LG VI,
wherein R
3 is selected from C
3-10cycloalkyl, C
3-10cycloalkenyl, C
1-10alkyl, C
2-10alkenyl, C
6-10aryl, C
1-10alkyleneC
6-10aryl and C
1-10alkyleneC
3-10cycloalkyl and LG is a leaving group, under conditions to provide the compound of
Formula V,
wherein in the compounds of Formulae I, V and VI, one or more available hydrogens
in R
1, R
2 and R
3 is/are optionally replaced with F and/or one or more of available atoms in R
1, R
2 and R
3 is/are optionally replaced with an isotopic label.
[0011] The oxazolidine ring in the compounds of Formula V can be cleaved under reducing
or hydrolysis conditions to provide further morphine analogs. For example, the reduction
of the compounds of Formula V provides the corresponding 14-O-methylated compounds
or 14-OH compounds. Hydrolysis of the compounds of Formula V provides the corresponding
14-OH, 17-NH compounds.
[0012] As a further example of the use of the compounds of Formula I in the preparation
of morphine analogs, hydrolysis of the compounds of Formula I under either acidic
or basic conditions provides the free phenols of Formula X:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R8 and R9 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R9 is not present; or
R8 and R9 are H, if in the compound of Formula I, R1 and R2 are a PG that is removed under the hydrolysis conditions; and
PG is a protecting group,
wherein in the compounds of Formula X, one or more available hydrogens in R8 and R9 is/are optionally replaced with F and/or one or more of available atoms in R8 and R9 is/are optionally replaced with an isotopic label.
[0013] Compounds of Formula X can be selectively alkylated at the 17-N to provide a wide
variety of morphine analogs.
[0014] The present application includes compounds of Formula V:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present;
PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion, and
one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label,
or a salt or solvate thereof.
[0015] The present application also includes compounds of Formula VII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other and when - -O represents =O, then H is not present;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion; and
one or more available hydrogens in R3 is/are optionally replaced with F and/or one or more of available atoms in R3 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
[0016] The present application also includes compounds of Formula VIII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R4 and R5 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R5 is not present;
PG is a protecting group; and
one or more available hydrogens in R3, R4 and R5 is/are optionally replaced with F and/or one or more of available atoms in R3, R4 and R5 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
[0017] Other features and advantages of the present application will become apparent from
the following detailed description. It should be understood, however, that the detailed
description and the specific examples while indicating embodiments of the application
are given by way of illustration only, since various changes and modifications within
the spirit and scope of the application will become apparent to those skilled in the
art from this detailed description.
DETAILED DESCRIPTION OF THE APPLICATION
I. Definitions
[0018] Unless otherwise indicated, the definitions and embodiments described in this and
other sections are intended to be applicable to all embodiments and aspects of the
application herein described for which they are suitable as would be understood by
a person skilled in the art.
[0019] As used in this application, the singular forms "a", "an" and "the" include plural
references unless the content clearly dictates otherwise. For example, an embodiment
including "an oxidizing agent" should be understood to present certain aspects with
one oxidizing agent, or two or more additional oxidizing agents.
[0020] In embodiments comprising an "additional" or "second" component, such as an additional
or second oxidizing agent, the second component as used herein is chemically different
from the other components or first component. A "third" component is different from
the other, first, and second components, and further enumerated or "additional" components
are similarly different.
[0021] The term "suitable" as used herein means that the selection of the particular compound
or conditions would depend on the specific synthetic manipulation to be performed,
and the identity of the molecule(s) to be transformed, but the selection would be
well within the skill of a person trained in the art. All process/method steps described
herein are to be conducted under conditions sufficient to provide the product shown.
A person skilled in the art would understand that all reaction conditions, including,
for example, reaction solvent, reaction time, reaction temperature, reaction pressure,
reactant ratio and whether or not the reaction should be performed under an anhydrous
or inert atmosphere, can be varied to optimize the yield of the desired product and
it is within their skill to do so.
[0022] In embodiments of the application, the compounds described herein have at least one
asymmetric centre. Where compounds possess more than one asymmetric centre, they may
exist as diastereomers. It is to be understood that all such isomers and mixtures
thereof in any proportion are encompassed within the scope of the present application.
It is to be further understood that while the stereochemistry of the compounds may
be as shown in any given compound listed herein, such compounds may also contain certain
amounts (e.g. less than 20%, suitably less than 10%, more suitably less than 5%) of
compounds of the application having alternate stereochemistry.
[0023] In understanding the scope of the present disclosure, the term "comprising" and its
derivatives, as used herein, are intended to be open ended terms that specify the
presence of the stated features, elements, components, groups, integers, and/or steps,
but do not exclude the presence of other unstated features, elements, components,
groups, integers and/or steps. The foregoing also applies to words having similar
meanings such as the terms, "including", "having" and their derivatives. The term
"consisting" and its derivatives, as used herein, are intended to be closed terms
that specify the presence of the stated features, elements, components, groups, integers,
and/or steps, but exclude the presence of other unstated features, elements, components,
groups, integers and/or steps. The term "consisting essentially of", as used herein,
is intended to specify the presence of the stated features, elements, components,
groups, integers, and/or steps as well as those that do not materially affect the
basic and novel characteristic(s) of features, elements, components, groups, integers,
and/or steps.
[0024] Terms of degree such as "substantially", "about" and "approximately" as used herein
mean a reasonable amount of deviation of the modified term such that the end result
is not significantly changed. These terms of degree should be construed as including
a deviation of at least ±5% of the modified term if this deviation would not negate
the meaning of the word it modifies.
[0025] The term "cyclodehydration reagent" as used herein refers to a reagent that facilitates
the cyclization of a compound of Formula III to a compound of Formula I via the loss
of one equivalent of H
2O under suitable conditions. The selection of a suitable cyclodehydration reagent
can be made by a person skilled in the art. In an embodiment of the application, the
cyclodehydration reagent is selected from Burgess reagent, TsCl, CrO
3, DCC, XtalFluor™ and carbonyldiimidazole. It is an embodiment that the cyclodehydration
reagent is Burgess reagent.
[0026] The term "Burgess reagent" as used herein refers to a reagent of the formula:

also known as methyl
N-(triethylammoniumsulfonyl)carbamate. This reagent is commercially available (for
example from Sigma Aldrich, St. Louis, MO, USA) or may be prepared from chlorosulfonylisocyanate
by treatment with methanol, followed by triethylamine in benzene.™
[0027] The term "counteranion" as used herein refers to a negatively charged species consisting
of a single element, or a negatively charged species consisting of a group of elements
connected by ionic and/or covalent bonds.
[0028] The term "acyl" as used herein, whether it is used alone or as part of another group,
means straight or branched chain, saturated acyl groups. The term C
1-6acyl means an acyl group having 1, 2, 3, 4, 5 or 6 carbon atoms (i.e. C(O)C
1-5alkyl). It is an embodiment of the application that, in the acyl groups, one or more,
including all of the available hydrogen atoms are optionally replaced with F or
2H and thus include, for example trifluoroacetyl and the like.
[0029] The term "alkyl" as used herein, whether it is used alone or as part of another group,
means straight or branched chain, saturated alkyl groups. The term C
1-6alkyl means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. It is an embodiment
of the application that, in the alkyl groups, one or more, including all, of the hydrogen
atoms are optionally replaced with F or
2H and thus include, for example trifluoromethyl, pentafluoroethyl and the like.
[0030] The term "alkylene" as used herein, whether it is used alone or as part of another
group, refers to a bivalent alkyl group.
[0031] The term "alkenyl" as used herein, whether it is used alone or as part of another
group, means straight or branched chain, unsaturated alkenyl groups. The term C
2-6alkenyl means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms and at least one
double bond. It is an embodiment of the application that, in the alkenyl groups, one
or more, including all, of the hydrogen atoms are optionally replaced with F or
2H and thus include, for example trifluoroethenyl, pentafluoropropenyl and the like.
[0032] The term "cycloalkyl" as used herein, whether it is used alone or as part of another
group, means cyclic, saturated alkyl groups. The term C
3-10cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
It is an embodiment of the application that, in the cycloalkyl groups, one or more,
including all, of the hydrogen atoms are optionally replaced with F or
2H.
[0033] The term "cycloalkenyl" as used herein, whether it is used alone or as part of another
group, means cyclic, unsaturated alkyl groups. The term C
3-10cycloalkenyl means a cycloalkenyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms
and at least one double bond. It is an embodiment of the application that, in the
cycloalkenyl groups, one or more, including all, of the hydrogen atoms are optionally
replaced with F or
2H.
[0034] The term "aryl" as used herein refers to cyclic groups that contain at least one
aromatic ring. In an embodiment of the application, the aryl group contains 6, 9 or
10 atoms, such as phenyl, naphthyl or indanyl. It is an embodiment of the application
that, in the aryl groups, one or more, including all, of the hydrogen atoms are optionally
replaced with F or
2H and thus include, for example pentafluorophenyl and the like.
[0035] The term "halo" as used herein refers to a halogen atom and includes F, Cl, Br and
I.
[0036] The term "oxidizing agent" as used herein means any compound or combination of compounds
that oxidizes a desired functional group(s) but does not otherwise react with or degrade
the substrate comprising the functional group(s). An oxidizing agent results in the
overall loss of electrons, or in the case of organic chemistry, hydrogen atoms from
the functional group.
[0037] The term "reducing agent" as used herein means any compound or combination of compounds
that reduces a desired functional group(s) but does not otherwise react with or degrade
the substrate comprising the functional group(s). A reducing agent results in the
overall gain of electrons, or in the case of organic chemistry, hydrogen atoms to
the functional group. It is an embodiment of the application that the reducing agent
is a metal hydride reducing agent.
[0038] The term "inert solvent" as used herein means a solvent that does not interfere with
or otherwise inhibit a reaction. Accordingly, the identity of the inert solvent will
vary depending on the reaction being performed. The selection of inert solvent is
within the skill of a person in the art. Examples of inert solvents include, but are
not limited to, benzene, toluene, tetrahydrofuran, ethyl ether, ethyl acetate, dimethyl
formamide (DMF), acetonitrile, C
1-6alkylOH (e.g. methanol, ethanol, n-propand, 2-propanol, n-butanol, butan-2-o1 and
2-methyl-1-propanol), diethylcarbonate, hexane and dimethylslfoxide (DMSO). Further
examples, can include aqueous solutions, such as water and dilute acids and bases,
and ionic liquids, provided that such solvents do not interfere with the reaction.
[0039] The term "solvent" includes both a single solvent and a mixture comprising two or
more solvents.
[0040] The term "available", as in "available hydrogen atoms" or "available atoms" refers
to atoms that would be known to a person skilled in the art to be capable of replacement
by either a fluorine atom (in the case of hydrogen atoms) or isotopic labels (in the
case of all atoms) using methods known in the art.
t-Boc as used herein refers to the group t-butyloxycarbonyl.
Ac as used herein refers to the group acetyl.
Ts (tosyl) as used herein refers to the group p-toluenesulfonyl
Ms as used herein refers to the group methanesulfonyl
TBDMS as used herein refers to the group t-butyldimethylsilyl.
TBDPS as used herein refers to the group t-butyldiphenylsilyl.
TMS as used herein refers to the group trimethylsilyl.
Tf as used herein refers to the group trifluoromethanesulfonyl.
Ns as used herein refers to the group naphthalene sulphonyl.
Bn as used herein refers to the group benzyl.
Fmoc as used herein refers to the group fluorenylmethoxycarbonyl.
mCPBA as used herein refers to meta-chloroperbenzoic acid.
[0041] The term "leaving group" or "LG" as used herein refers to a group that is readily
displaceable by a nucleophile, for example, under nucleophilic substitution reaction
conditions. Examples of suitable leaving groups include, but are not limited to, halo,
Ms, Ts, Ns, Tf, C
1-6acyl, and the like.
[0042] The terms "protective group" or "protecting group" or "PG" or the like as used herein
refer to a chemical moiety which protects or masks a reactive portion of a molecule
to prevent side reactions in those reactive portions of the molecule, while manipulating
or reacting a different portion of the molecule. After the manipulation or reaction
is complete, the protecting group is removed under conditions that do not degrade
or decompose the remaining portions of the molecule. The selection of a suitable protecting
group can be made by a person skilled in the art. Many conventional protecting groups
are known in the art, for example as described in "
Protective Groups in Organic Chemistry" McOmie, J.F.W. Ed., Plenum Press, 1973, in
Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley
& Sons, 3rd Edition, 1999 and in
Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas). Examples of suitable protecting groups include, but are not limited to t-Boc,
Ac, Ts, Ms, silyl ethers such as TMS, TBDMS, TBDPS, Tf, Ns, Bn, Fmoc, dimethoxytrityl,
methoxyethoxymethyl ether, methoxymethyl ether, pivaloyl, p-methyoxybenzyl ether,
tetrahydropyranyl, trityl, ethoxyethyl ethers, carbobenzyloxy, benzoyl and the like.
[0043] The expression "proceed to a sufficient extent" as used herein with reference to
the reactions or process steps disclosed herein means that the reactions or process
steps proceed to an extent that conversion of the starting material or substrate to
product is maximized. Conversion may be maximized when greater than about 5, 10, 15,
20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the starting
material or substrate is converted to product.
II. Methods of the Application
[0044] The present application includes a process for the preparation of a compound of Formula
I:

comprising:
- (a) reacting a compound of Formula II with an oxidizing agent under conditions to
provide a compound of Formula III:

and
- (b) reacting the compound of Formula III with a cyclodehydration reagent under conditions
to provide the compound of Formula I,
wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present; and
PG is a protecting group; and
wherein in the compounds of Formulae I, II and III, one or more available hydrogens
in R1 and R2 is/are optionally replaced with F and/or one or more of available atoms in R1 and R2 is/are optionally replaced with an isotopic label.
[0045] In an embodiment of the application, R
1 and R
2 are independently selected from C
1-6alkyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
1-6alkyleneC
6-10aryl, C
1-6alkyleneC
3-6cycloalkyl and PG. In a further embodiment of the application, R
1 and R
2 are independently selected from Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG. It is an embodiment
of the application that PG is an alkyl acetate, such as acetyl.
[0046] In an embodiment, the compound of Formula II is selected from a compound of Formula
II(a), II(b) and II(c):

wherein
---- represents a single or double bond;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, and PG is a protecting group, which provide, respectively, a compound
of the Formula I(a), I(b) and I(c) using the process of the present application:

wherein
---- represents a single or double bond;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, and PG is a protecting group; and
wherein in the compounds of Formulae I(a), I(b), I(c), II(a), II(b) and II(c), one
or more available hydrogens in R1 and R2 is/are optionally replaced with F and/or one or more of available atoms in R1 and R2 is/are optionally replaced with an isotopic label.
[0047] Oxidation of the compounds of Formula II to the compounds of Formula III is performed
using any suitable oxidizing agent. In an embodiment of the application, the oxidizing
agent is a peroxide or a peracid. In another embodiment, the peracid is m-chloroperbenzoic
acid (mCPBA). Conditions to oxidize tertiary amines to the corresponding N-oxides
are known in the art. Other exemplary oxidizing agents include hydrogen peroxide,
peracetic acid, t-butylhydroperoxide and magnesium monoperoxyphthalate.
[0048] In an embodiment of the application, the cyclodehydration reagent is Burgess reagent.
Other cyclodehydration agents were examined in the place of the Burgess reagent. Thus
oxycodone-
N-oxide also yielded oxazolidine on treatment with TsCl (30%), CrO
3 (44%) and DCC (50%). Treatment of the
N-oxide with CS
2 or SeO
2 resulted only in its re-conversion to oxycodone. Other reagents that may be used
in place of Burgess reagent are XtalFluor™ and carbonyldiimidazole, both of which
are commercially available, for example from Sigma-Aldrich, USA.
[0049] In an embodiment of the application, the conditions to provide the compounds of Formula
I from the compounds of Formula III using a cyclodehydration reagent comprise a temperature
of about -50°C to about 50°C, in an inert solvent or mixture of solvents for a time
for the conversion of the compound of Formula III to the compound of Formula I to
proceed to a sufficient extent, for example from about 0.5 hours to about 48 hours,
or about 2 hours to about 10 hours. In an embodiment, the molar ratio of cyclodehydration
reagent to the compound of Formula III is about 1.5:1 to about 1:1.
[0050] In a representative example of the process of the present application, the reaction
of oxycodone N-oxide, derived from oxycodone (compound of Formula II(b), wherein R
1 = Me and
---- is a single bond), with the Burgess reagent was examined and a clean conversion to
the corresponding oxazolidine (compound of Formula I(b), wherein R
1 = Me and
---- is a single bond) was obtained, providing significantly higher yields than that quoted
in the Smith procedure shown in Scheme 2.
[0051] The compounds of Formula I, wherein R
1 and/or R
2 are PG, can be deprotected to provide the corresponding free hydroxy compounds, that
is, compounds of Formula IV:
wherein ---- represents a single or double bond, provided that two double bonds are not adjacent
to each other and when - -O represents =O, then the H is not present.
[0052] As noted above, the compounds of Formula I are useful for the preparation of a variety
of different morphine analogs:
(i) Quaternary Salts of the Compounds of Formula I
[0053] Compounds of Formula I have been converted to the corresponding quaternary salts
by reaction with an alkylating reagent. Therefore, the present application also includes
a process for preparing compounds of Formula V:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present;
PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl; and
X is a counteranion, comprising
reacting a compound of Formula I:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present; and
PG is a protecting group,
with an alkylating reagent of Formula VI:
R3-LG VI,
wherein
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl, and
LG is a leaving group, under conditions to provide the compound of Formula V,
wherein in the compounds of Formulae I, V and VI, one or more available hydrogens
in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label.
[0054] In an embodiment, R
3 in the compounds of Formula V and VI is selected from C
1-6alkyl, C
2-6alkenyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
3-6cycloalkenyl, C
1-6alkyleneC
6-10aryl, and C
1-6alkyleneC
3-6cycloalkyl. In a further embodiment of the application, R
3 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
[0055] In an embodiment of the application, LG in the compounds of Formula VI is any suitable
leaving group, for example, halo, Ms, Ts, Ns, Tf, C
1-6acyl, and the like. In a specific embodiment LG is halo, such as Br.
[0056] In another embodiment, X is the anion of LG, for example Br
-. In a further embodiment, X is LG
- and the process further comprises a hydrolysis step to convert LG
- to OH
-. Hydrolysis can be performed, for example, by treating the compound of Formula V
with a base in an aqueous, alcoholic solvent system.
[0057] In an embodiment, the compound of Formula V is selected from a compound of Formula
V(a), V(b) and V(c):

wherein
---- represents a single or double bond;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, and PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion, and
one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label.
[0058] The compounds of Formula V, wherein R
1 and/or R
2 are PG, may be deprotected to provide the corresponding free OH compounds, that is
compounds of Formula VII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other and when - -O represents =O, then H is not present;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion; and
one or more available hydrogens in R3 is/are optionally replaced with F and/or one or more of available atoms in R3 is/are optionally replaced with an isotopic label.
[0059] The oxazolidine ring in the compounds of Formula V can be cleaved using either reducing
or hydrolysis (acidic or basic) conditions. Under reducing conditions, the compounds
of the Formula V provide compounds of the Formula VIII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R4 and R5 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R5 is not present, or
R4 and R5 are H if, in the compounds of Formula V, R1 and R2 are a PG that is removed under the reducing conditions;
PG is a protecting group that is not removed under the reducing conditions, and
one or more available hydrogens in R3, R4 and R5 is/are optionally replaced with F and/or one or more of available atoms in R3, R4 and R5 is/are optionally replaced with an isotopic label.
[0060] Under some reducing conditions, the compounds of the Formula V can provide compounds
of the Formula VIII(d):

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R4 and R5 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R5 is not present, or
R4 and R5 are H if, in the compounds of Formula V, R1 and R2 are a PG that is removed under the reducing conditions;
PG is a protecting group that is not removed under the reducing conditions, and
one or more available hydrogens in R3, R4 and R5 is/are optionally replaced with F and/or one or more of available atoms in R3, R4 and R5 is/are optionally replaced with an isotopic label.
[0061] In an embodiment of the application, R
4 and R
5 in the compounds of Formula VIII(d) are independently selected from C
1-6alkyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
1-6alkyleneC
6-10aryl, C
1-6alkyleneC
3-6cycloalkyl and PG. In a further embodiment of the application, R
4 and R
5 are independently selected from Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG.
[0062] Under hydrolysis conditions, the compounds of the Formula V provide compounds of
the Formula IX:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R6 and R7 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R7 is not present, or
R6 and R7 are H if, in the compounds of Formula V, R1 and R2 are a PG that is removed under the hydrolysis conditions;
PG is a protecting group that is not removed under the hydrolysis conditions, and
one or more available hydrogens in R3, R6 and R7 is/are optionally replaced with F and/or one or more of available atoms in R3, R6 and R7 is/are optionally replaced with an isotopic label.
[0063] In an embodiment of the application, R
6 and R
7 in the compounds of Formula IX are independently selected from C
1-6alkyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
1-6alkyleneC
6-10aryl, C
1-6alkyleneC
3-6cycloalkyl and PG. In a further embodiment of the application, R
6 and R
7 are independently selected from Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG.
[0064] In an embodiment, the reducing conditions to provide the compounds of Formula VIII
comprise treating the compounds of Formula V with a suitable reducing agent, such
as metal hydride reducing agents, optionally in the presence of a Lewis acid, for
a time and temperature for the conversion of the compound of Formula V to the compound
of Formula VIII to proceed to a sufficient extent, for example at about -100°C to
about 100°C for about 0.5 hours to about 48 hours.
[0065] In a further embodiment, the hydrolysis conditions to provide the compounds of Formula
IX comprise treating the compounds of Formula V under suitable acidic (for example
acetic acid/ammonia buffer) or basic (for example ammonium bicarbonate/ammonia) conditions
for a time and temperature for the conversion of the compound of Formula V to the
compound of Formula IX to proceed to a sufficient extent, for example at about -100°C
to about 100°C for about 0.5 hours to about 48 hours.
[0066] In a particular embodiment, PG is a protecting group that is removed under conditions
to hydrolyze the compound of Formula V to the compound of Formula IX. For example,
when PG is an alkyl carbonate, hydrolysis under basic conditions hydrolyzes the oxazolidine
and removes the protecting group simultaneously. In another embodiment, when PG is
an alkyl acetate, hydrolysis under acidic conditions hydrolyzes the oxazolidine and
removes the protecting group simultaneously. A person skilled in the art would appreciate
that other protecting groups removable under reducing, acidic or basic conditions
compatible with the compounds of Formula V, VIII and IX can also be used.
[0067] In an alternate embodiment, R
1 and R
2 in the compounds of Formula V are not a PG that is removed under the reducing or
hydrolysis conditions, and the compounds of Formula VIII and IX are further treated
under conditions to remove the PG group to provide the corresponding free hydroxy
compounds (i.e. compounds of Formula VIII wherein R
4 and R
5 are H and compounds of Formula IX wherein R
6 and R
7 are H).
(ii) Hydrolysis of the Compounds of Formula I
[0068] Hydrolysis of the compounds of Formula I under either acidic or basic conditions
provides the free phenols of Formula X:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R8 and R9 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R9 is not present; or
R8 and R9 are H, if in the compound of Formula I, R1 and R2 are a PG that is removed under the hydrolysis conditions; and
PG is a protecting group,
wherein in the compounds of Formula X, one or more available hydrogens in R8 and R9 is/are optionally replaced with F and/or one or more of available atoms in R8 and R9 is/are optionally replaced with an isotopic label.
[0069] In an embodiment of the application, R
8 and R
9 in the compounds of Formula X are independently selected from C
1-6alkyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
1-6alkyleneC
6-10aryl, C
1-6alkyleneC
3-6cycloalkyl and PG. In a further embodiment of the application, R
8 and R
9 are independently selected from Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG.
[0070] In a particular embodiment, PG in the compounds of Formula I is a protecting group
that is removed under conditions to hydrolyze the compound of Formula I to the compound
of Formula X. For example, when PG is an alkyl carbonate, hydrolysis under basic conditions
hydrolyzes the oxazolidine and removes the protecting group simultaneously. In another
embodiment, when PG is an alkyl acetate, hydrolysis under acidic conditions hydrolyzes
the oxazolidine and removes the protecting group simultaneously. A person skilled
in the art would appreciate that other protecting groups removable under acidic or
basic conditions compatible with the compounds of Formula I and X can also be used.
In an alternate embodiment, PG is a protecting group that is not removed under conditions
to hydrolyze the compound of Formula I to the compound of Formula X and is optionally
removed in a separate step after the preparation of the compound of Formula X.
[0071] The compounds of Formula X are selectively alkylated at N-17 by reaction with a compound
of the Formula R
10-LG
1 (XI), wherein LG
1 is a leaving group and R
10 is selected from C
3-10cycloalkyl, C
3-10cycloalkenyl, C
1-10alkyl, C
2-10alkenyl, C
6-10aryl, C
1-10alkyleneC
6-10aryl and C
1-10alkyleneC
3-10cycloalkyl under standard alkylation conditions to provide compounds of Formula XII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R8 and R9 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R9 is not present;
PG is a protecting group;
R10 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl; and
one or more available hydrogens in R8, R9 and R10 is/are optionally replaced with F and/or one or more of available atoms in R8, R9 and R10 is/are optionally replaced with an isotopic label.
[0072] When R
8 and/or R
9 in the compounds of Formula XII is PG, it is an embodiment of the present application
that the compounds of Formula XII are further treated under conditions to remove the
PG to provide the corresponding free hydroxy compounds (i.e. compounds of Formula
XII wherein R
8 and/or R
9 are H).
[0073] In an embodiment, R
10 in the compounds of Formula XII is selected from C
1-6alkyl, C
2-6alkenyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
3-6cycloalkenyl, C
1-6alkyleneC
6-10aryl, and C
1-6alkyleneC
3-6cycloalkyl. In a further embodiment of the application, R
10 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
[0074] In this embodiment, it is possible to prepare the known morphine analogs, naltrexone
(R
10 is cyclopropylmethyl), nalbuphine (R
10 is cyclobutylmethyl) and naloxone (R
10 is allyl). In each of these latter compounds, R
1 is H, R
2 is not present and ring C (i.e. the bottom ring) has the structure:

[0075] In a specific example of the present application, oxymorphone was converted to naltrexone
or naloxone in just three operations in an overall yield of 55-65% using a process
of the present application.
[0076] The processes of the present application may be performed using continuous or batch
processes. For commercial scale preparations continuous processes are suitable. Methods
of performing chemical processes in continuous or batch modes are known in the art.
When continuous processes are used, the reaction temperature and/or pressure may be
higher than those used in batch processes.
III. Compounds of the Application
[0077] The present application includes compounds of Formula V:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present;
PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion, and
one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label,
or a salt or solvate thereof.
[0078] In an embodiment of the application, R
1 and R
2 in the compounds of Formula V are independently selected from C
1-6alkyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
1-6alkyleneC
6-10aryl, C
1-6alkyleneC
3-6cycloalkyl and PG. In a further embodiment of the application, R
1 and R
2 are independently selected from Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG. It is an embodiment
of the application that PG is an alkyl acetate, such as acetyl.
[0079] In another embodiment, R
3 in the compounds of Formula V is selected from C
1-6alkyl, C
2-6alkenyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
3-6cycloalkenyl, C
1-6alkyleneC
6-10aryl, and C
1-6alkyleneC
3-6cycloalkyl. In a further embodiment of the application, R
3 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
[0080] In another embodiment of the present application, X in the compounds of Formula V
is OH-, Br
- or Cl
-.
[0081] In an embodiment, the compound of Formula V is selected from a compound of Formula
V(a), V(b) and V(c):

wherein
---- represents a single or double bond;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, and PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion, and
one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label,
or a salt or solvate thereof.
[0082] The present application also includes compounds of Formula VII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other and when - -O represents =O, then H is not present;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion; and
one or more available hydrogens in R3 is/are optionally replaced with F and/or one or more of available atoms in R3 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
[0083] In another embodiment, R
3 in the compounds of Formula VII is selected from C
1-6alkyl, C
2-6alkenyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
3-6cycloalkenyl, C
1-6alkyleneC
6-10aryl, and C
1-6alkyleneC
3-6cycloalkyl. In a further embodiment of the application, R
3 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
[0084] In another embodiment of the present application, X in the compounds of Formula VII
is OH
-, Br
- or Cl
-.
[0085] In a further embodiment, the compounds of Formula VII are selected from a compound
of Formula VII(a), VII(b) and VII(c):

wherein
---- represents a single or double bond;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion; and
one or more available hydrogens in R3 is/are optionally replaced with F and/or one or more of available atoms in R3 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
[0086] The present application also includes compounds of Formula VIII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R4 and R5 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R5 is not present;
PG is a protecting group; and
one or more available hydrogens in R3, R4 and R5 is/are optionally replaced with F and/or one or more of available atoms in R3, R4 and R5 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
[0087] In an embodiment, R
3 in the compounds of Formula VIII is selected from C
1-6alkyl, C
2-6alkenyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
3-6cycloalkenyl, C
1-6alkyleneC
6-10aryl, and C
1-6alkyleneC
3-6cycloalkyl. In a further embodiment of the application, R
3 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
[0088] In an embodiment of the application, R
4 and R
5 in the compounds of Formula VIII are independently selected from H, C
1-6alkyl, phenyl, naphthyl, indanyl, C
3-6cycloalkyl, C
1-6alkyleneC
6-10aryl, C
1-6alkyleneC
3-6cycloalkyl and PG. In a further embodiment of the application, R
4 and R
5 are independently selected from H, Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG. It is an embodiment
of the application that PG is an alkyl acetate, such as acetyl.
[0089] In a further embodiment, the compounds of Formula VIII are selected from a compound
of Formula VIII(a), VIII(b) and VIII(c):

wherein
---- represents a single or double bond;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R4 and R5 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG;
PG is a protecting group; and
one or more available hydrogens in R3, R4 and R5 is/are optionally replaced with F and/or one or more of available atoms in R3, R4 and R5 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
[0090] The following non-limiting examples are illustrative of the present application:
EXAMPLES
Example 1: General procedure for N-oxidations
[0091] To a solution of oxycodone, oxymorphone, or 3-
O-Ac-oxymorphone (1g scale) in dichloromethane (10 mL) cooled to 4 °C was added
mCPBA (1 eq., 77% purity). The reaction mixture was stirred for 10 min and then added
dropwise to vigorously stirred diethyl ether (100 mL). A white precipitate of product
was filtered off to give nearly quantitative yield.
(a) Oxycodone N-oxide
[0092]

[0093] R
F= 0.26 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]
D20 = -167.6 (c 1, CHCl
3); mp = 220 °C (decomposition, Et
2O); IR (KBr, cm
-1) v 3426, 3018, 2997, 2956, 2932, 2862, 2832, 2312, 2243, 2160, 2133, 1900, 1723,
1632, 1606, 1533, 1499, 1461, 1436, 1342, 1312, 1256, 1160, 1017, 976, 933, 816;
1H NMR (CDCl
3, 300 MHz) δ 6.76 (d, 1 H,
J=8.4 Hz), 6.67 (d, 1H,
J=7.8 Hz), 4.78 (s, 1H), 3.92 (s, 3H), 3.62 (d, 1H,
J=5.1 Hz), 3.34 (s, 3H), 3.31-3.10 (m, 6H), 2.24 (ddd, 1 H,
J=3.0, 3.0, 14.4 Hz), 1.97 (ddd, 1 H,
J=3.0, 4.8, 12.6 Hz), 1.70 (dd, 1 H,
J=3.3, 12.5 Hz), 1.61 (ddd, 1 H,
J=3.3, 12.9, 14.4 Hz);
13C NMR (CDCl
3, 75 MHz) δ 207.74, 145.32, 143.96, 129.28, 120.33, 120.08, 115.75, 89.93, 75.78,
72.23, 61.69, 59.54, 59.85, 49.94, 34.93, 32.89, 28.68, 25.80; MS (+El)
m/
z (%) 332 (100), 314 (29); HRMS (+FAB) calcd for C
18H
22NO
5: 332.14980. Found 332.14636.
(b) 3-Acetyl-oxymorphone N-oxide
[0094]

[0095] Oxymorphone (600 mg; 1.99 mmol) was dissolved in tetrahydrofuran (8 mL). Solid K
2CO
3 (275 mg; 1.99 mmol) and acetic anhydride (188 µL, 1.99 mmol) were then added and
the reaction mixture was stirred at room temperature for 1.5 hours. TLC (95/5 dichloromethane:methanol,
double development) showed only traces of starting material. The crude material was
subjected to the oxidation protocol without isolation to furnish the
N-oxide as a solid: [α]
D20 = -189.33 (c 1, CHCl
3); mp = 160 °C (CHCl
3); IR (KBr, cm
-1) v 3449, 2968, 2938, 1764, 1726, 1685, 1654, 1627, 1495, 1444, 1373, 1287, 1219,
1193, 1161, 1111, 1044, 931, 629;
1H NMR (CDCl
3, 300 MHz) δ 12.25 (bs, 1 H), 6.91 (d, 1 H,
J=8.4 Hz), 6.72 (d, 1 H,
J=8.1 Hz), 4.80 (s, 1H), 3.60 (d, 1H,
J=5.1 Hz), 3.36-3.03 (m, 9H), 2.31 (s, 3H), 2.23 (ddd, 1H,
J=3.0, 3.0, 14.7 Hz), 1.96 (ddd, 1 H,
J=3.0, 4.8, 12.6 Hz), 1.71 (dd, 1 H,
J=3.9, 11.4 Hz), 1.58 (ddd, 1 H,
J=3.6, 14.1, 14.1 Hz);
13C NMR (CDCl
3, 75 MHz) δ 206.97, 168.31, 148.23, 133.53, 129.93, 125.90, 124.10, 119.84, 90.15,
75.44, 72.14, 61.51, 59.49, 49.77, 34.84, 32.62, 28.94, 25.82, 20.74; MS (FAB+)
m/
z (%) 360 (100), 342 (20); HRMS (+FAB) calcd for C
19H
22NO
6: 360.14471. Found 360.14441.
(c) 3-Ethoxycarbonyl-oxymorphone N-oxide
[0096]

[0097] Oxymorphone (100 mg, 0.33 mmol) was suspended in ethyl acetate (1 mL) and ethylchloroformate
(32 µL, 33 mmol) was added dropwise prior to addition of triethylamine (46 µL, 33
mmol). The reaction mixture (white suspension) was stirred for 1 hour at room temperature.
TLC analysis (dichloromethane/methanol/ammonia (90:8:2)) showed essentially clean
conversion to the product (R
f=0.70), which was immediately subjected without isolation to the oxidation protocol
to yield the titled compound as a solid: R
F = 0.28 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]
D20 = -50 → -120 (
c 1, CH
2Cl
2) dynamic rotation; mp = 112-115 °C (
i-PrOH); IR (KBr, cm
-1) v 3432, 3062, 2980, 2935, 2361, 2343, 1768, 1728, 1627, 1497, 1445, 1371, 1261,
1195, 1164, 1065, 1002, 931, 864, 738;
1H NMR (CDCl
3, 600 MHz) δ 7.01 (d, 1 H,
J=8.4 Hz), 6.74 (d, 1 H,
J=7.8 Hz), 4.86 (s, 1 H), 4.32 (m, 2H), 3.69 (d, 1 H,
J=6.0 Hz), 3.38-3.35 (m, 5H), 3.27 (ddd, 1 H,
J= 4.2, 13.2, 13.2 Hz), 3.22 (dd, 1 H,
J=5.4, 19.86 Hz), 3.16 (ddd, 1H,
J=4.8, 14.4, 14.4 Hz), 3.13 (ddd, 1H,
J=4.2, 12.0, 12.0 Hz), 2.26 (ddd, 1H,
J=3.0, 3.0, 14.4 Hz), 2.02 (ddd, 1H,
J=3.0, 4.8, 13.2 Hz), 1.74 (dd, 1H,
J=1.8, 13.2 Hz), 1.61 (ddd, 1 H,
J=3.0, 14.4, 14.4 Hz), 1.39 (t, 3H,
J=7.2 Hz);
13C NMR (CDCl
3, 125 MHz) δ 206.65, 152.66, 148.14, 134.09, 130.15, 126.16, 123.83, 119.90, 90.26,
75.47, 72.22, 65.36, 61.54, 59.44, 49.75, 34.85, 32.56, 28.98, 25.86, 14.14; MS (+El)
m/
z (%) 390 (100); HRMS (+El) calcd for C
20H
24NO
7: 390.15528. Found 390.15495.
Example 2: (5aR,8aS,11aR,11bS)-2-methoxy-5,5a,9,10-tetrahydro-6,11b-ethano-7H-furo[2',3',4',5';4,5]phenanfhro[9,8a-d]oxazo/-11(11aH)-one
[0098]

[0099] Oxycodone N-oxide (Example 1 a, 150 mg; 0.45 mmol) was dissolved in dichloromethane
(10 mL). The reaction mixture was cooled to -20 to -25 °C in an acetone/N
2(
l) bath and Burgess reagent (150 mg; 0.63 mmol) was added as a solid in one portion.
The reaction mixture was stirred for 5 hours and allowed to warm to room temperature.
At -5 °C the color of the reaction mixture changed from colorless to yellowish. The
mixture was then diluted with dichloromethane (50 mL) and washed with NaHCO
3 (2 x 10 mL). The aqueous layer was re-extracted with dichloromethane (15 mL) and
the combined organic layers were dried with MgSO
4 and concentrated to yield 157 mg of the titled oxazolidine as a yellow solid. The
compound was not stable on silica, low-melting, hygroscopic solid; data was collected
at 90% purity.
[0100] R
F = 0.7 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]
D20 = -113.3 (
c 1, CHCl
3); IR (KBr, cm
-1) v 2926, 2854, 1728, 1635, 1610, 1506, 1441, 1385, 1335, 1313, 1277, 1257, 1165,
1088, 1074, 1003, 951, 926, 895, 779;
1H NMR (CDCl
3, 600 MHz) δ 6.78 (d, 1H,
J=8.4 Hz), 6.72 (d, 1 H,
J=8.1 Hz), 4.75 (d, 1 H,
J=6.0 Hz), 4.71 (d, 1 H,
J=6.0 Hz), 4.69 (s, 1 H), 3.91 (s, 3H), 3.35 (d, 1 H,
J=18.6 Hz), 3.27 (d, 1 H,
J=7.8 Hz), 3.16 (dd, 1 H,
J=7.8, 18.6 Hz), 2.92 (ddd, 1 H,
J=4.8, 14.4, 14.4 Hz), 2.86-2.80 (m, 2H), 2.43 (ddd, 1 H,
J=3.0, 3.0, 10.5 Hz), 2.39 (m, 1H), 2.00 (ddd, 1H,
J=3.9, 3.9, 13.8 Hz), 1.68 (ddd, 1H,
J=3.0, 3.0, 14.7 Hz), 1.56 (m, 1H);
13C NMR (CDCl
3, 125 MHz) δ 207.15, 144.74, 142.86, 129.10, 123.20, 120.03, 115.19, 91.01, 86.49,
77.21, 64.10, 56.78, 52.58, 44.35, 37.14, 34.12, 30.56, 26.80; MS (+El)
m/
z (%) 313 (100), 257 (8), 229 (8); HRMS (+El) calcd for C
18H
19NO
4: 313.13141. Found 313.13128.
Example 3: (5aR,8aS,11aR,11bS)-2-Acetoxy-5,5a,9,10-tetrahydro-6,11b-ethano-7H-furo[2',3',4',5':4,5]phenanthro[9,8a-d]oxazol-11(11aH)-one,
one-pot protocol
[0101]

[0102] Oxymorphone (600 mg; 1.99 mmol) was dissolved in tetrahydrofuran (8 mL). Solid K
2CO
3 (275 mg; 1.99 mmol) and acetic anhydride (188 µL, 1.99 mmol) were then added and
the reaction mixture was stirred at room temperature for 1.5 hours. TLC (95/5 dichloromethane:methanol,
double development) showed only traces of starting material. The reaction mixture
was then cooled to ∼4°C in an ice-bath, and a cold (4 °C) solution of
mCPBA (446 mg; 1.99 mmol; 77% purity) in dichloromethane (6 mL) was added dropwise
over a period of 1 minute. [The solution of
mCPBA was prepared by dissolving 669 mg mCPBA (77%) in dichloromethane (9 mL) and adding
MgSO
4 (670 mg). The mixture was agitated several times over a period of 30 min and cooled
in an ice-bath to 4 °C]. After 1 hour stirring, a white precipitate of
N-oxide formed and the reaction mixture was cooled to -20°C. Burgess reagent (593 mg,
2.49 mmol) in dichloromethane (7 mL) was then cannulated at -20 °C into the reaction
mixture over a period of 2 minutes. The reaction mixture was allowed to warm to 10
°C (3 h total reaction time) and then diluted with ethyl acetate (100 mL), and washed
with NaHCO
3 solution (2 x 20 mL). The combined aqueous layer was reextracted with ethylacetate
(2 x 20 mL) and the combined organic layer was dried with MgSO
4, filtered and concentrated to yield 636 mg (93%) of reasonably pure (92-95%) material.
Crystallyzation of the product from a mixture of EtOH/
i-PrOH 1:1 (2 mL), temperature regime of 25 °C to 5-10 °C, afforded 520 mg (76%) of
product. Repetition of the experiment on a scale of one gram yielded 78% of the titled
compound as a solid.
[0103] R
F = 0.7 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]
D20 = -84.1 (
c 1, CHCl
3); mp = 179-182°C (
i-PrOH); IR (KBr, cm
-1) v 2954, 2892, 2864, 2834, 1765, 1722, 1624, 1494, 1445, 1370, 1339, 1317, 1216,
1201, 1185, 1158, 1073, 1009, 958, 930, 889, 781;
1H NMR (CDCl
3, 600 MHz) δ 6.90 (d, 1 H,
J=8.2 Hz), 6.76 (d, 1 H,
J=8.4 Hz), 4.73 (d, 1 H,
J=6.0 Hz), 4.70 (d, 1 H,
J=6.0 Hz), 4.69 (s, 1 H), 3.37 (d, 1 H,
J=19.2 Hz), 3.27 (d, 1 H,
J=7.8 Hz), 3.17 (dd, 1 H,
J=7.8, 19.2 Hz), 2.89 (ddd, 1 H,
J=4.8, 14.4, 14.4 Hz), 2.80 (m, 2H), 2.45-2.30 (m, 5H), 1.98 (ddd, 1H,
J=3.3, 4.2, 13.8 Hz), 1.67 (ddd, 1H,
J=3.1, 14.4, 14.4 Hz), 1.56 (m, 1H);
13C NMR (CDCl
3, 150 MHz) δ 206.36, 168.57, 147.49, 132.45, 129.76, 128.65, 123.49, 119.97, 91.25,
86.53, 77.00, 63.95, 52.40, 44.23, 37.09, 34.09, 30.28, 27.13, 20.83; MS (+El) m/z
(%) 341 (8), 299 (100), 243 (7); HRMS (+EI) calcd for C
19H
19NO
5: 341.12632. Found 341.12606.
Example 4: (5aR,8aS,11aR,11bS)-2-[(Ethoxycarbonyl)oxy]-5,5a,9,10-tetrahydro-6,11b-ethano-7H-furo[2',3',4',5':4,5]phenanfhro[9,8a-d]oxazo/-11(1aH)-one, one-pot protocol
[0104]

[0105] Oxymorphone (100 mg, 0.33 mmol) was suspended in ethyl acetate (1 mL) and ethylchloroformate
(32 µL, 33 mmol) was added dropwise prior to addition of triethylamine (46 µL, 33
mmol). The reaction mixture (white suspension) was stirred for one hour at room temperature.
TLC analysis (dichloromethane/methanol/ammonia (90:8:2)) showed essentially a clean
conversion to the ethyl carbonate-protected oxymorphone.
[0106] The crude reaction mixture containing the carbonate was then cooled to 4 °C in an
ice-bath, and a 1 mL aliquot of a solution of
mCPBA [The solution was prepared as follows:
mCPBA (148 mg, 77% peroxide content, 0.66 mmol) was dissolved in ethyl acetate (2 mL)
and MgSO
4 (140 mg) was added. The solution was dried 30 min and then cooled to 4 °C] was added
dropwise. The reaction mixture was stirred for one hour at 4 °C. TLC analysis (dichloromethane/methanol/ammonia
(90:8:2) showed essentially clean conversion to the carbonate-protected product R
f =0.28. The reaction mixture was then cooled to -25 °C and Burgess reagent was added
in one portion as a solid. The mixture was then allowed to reach room temperature
in approximately 2-3 hours as the color changed from a white to a yellow suspension.
The reaction mixture was then diluted with ethyl acetate (10 mL), washed with NaHCO
3 (2 x 4 mL), and the aqueous layer was re-extracted with ethyl acetate (5 mL). The
combined organic layers were dried over MgSO
4 and concentrated to yield 125 mg of crude oxazolidine (85-90% purity) in ∼84% yield
as a low melting solid:
[0107] R
F= 0.70 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]D
20= -64.19 (
c 1, CHCl
3); mp = low-melting solid; IR (KBr, cm
-1) v 3448, 2960, 2945, 2924, 2887, 1764, 1728, 1626, 1498, 1448, 1372, 1341, 1257,
1237, 1208, 1164, 1073, 1027, 931, 783;
1H NMR (CDCl
3, 600 MHz) δ 6.99 (d, 1 H,
J=8.4 Hz), 6.78 (d, 1 H,
J=7.8 Hz), 4.76 (d, 1 H,
J=6.0 Hz), 4.74 (s, 1 H), 4.72 (d, 1 H,
J=5.4 Hz), 4.35-4.31 (m, 2H), 3.38 (d, 1 H,
J=18.6 Hz), 3.29 (d, 1 H,
J=8.4 Hz), 3.19 (dd, 1H,
J=7.8, 19.2 Hz), 2.90 (ddd, 1H,
J=4.8, 14.4, 14.4 Hz), 2.82 (bd, 2H,
J=8.4 Hz), 2.42 (bd, 1H,
J=13.2 Hz), 2.39 (m, 1H), 1.99 (ddd, 1H,
J=
∼1.0, ∼1.0, 13.8 Hz), 1.69 (ddd, 1H,
J=∼1.0, 13.2, 13.2 Hz), 1.58 (d, 1H,
J=12.6 Hz), 1.39 (t, 3H,
J=7.2 Hz);
13C NMR (CDCl
3, 150 MHz) δ 206.19, 152.91, 147.38, 132.97, 130.00, 128.95, 123.15, 120.02, 91.35,
86.50, 65.15, 63.91, 52.37, 44.20, 37.07, 34.11, 30.23, 27.13, 14.16, 1.03; MS (+EI)
m/
z (%) 371 (13), 327 (14), 299 (100); HRMS (+EI) calcd for C
20H
21NO
6: 371.13689. Found 371.13697.
[0108] Analytical samples of intermediates (protected oxymorphone and protected oxymorphone
N-oxide) were prepared in a stepwise manner and purified by column chromatography.
An analytical sample of the oxazolidine from Example 4 was prepared from the protected
oxymorphone. The N-oxidation and treatment with the Burgess reagent was performed
in two steps in 95% yield (95% purity). Crystallization of the product from Example
4 was not possible because it is a low-melting hygroscopic solid).
Oxymorphone O-ethyl carbonate:
[0109] R
F = 0.75 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]
D20 = 146.84 (
c 1, CH
2Cl
2); mp = 156-157 °C (
i-PrOH); IR (KBr, cm
-1) v 3433, 2982, 2936, 2907, 2870, 2811, 1755, 1727, 1627, 1498, 1447, 1373, 1348,
1321, 1197, 1165, 1032, 934, 782;
1H NMR (CDCl
3, 600 MHz) δ 6.92 (d, 1 H,
J=8.4 Hz), 6.71 (d, 1 H,
J=7.8 Hz), 5.09 (bs, 1 H), 4.72 (s, 1 H), 4.32 (m, 2H), 3.20 (d, 1H,
J=18.6 Hz), 3.02 (ddd, 1H,
J=4.8, 14.4, 14.4 Hz), 2.90 (d, 1H,
J=6.0 Hz), 2.60 (dd, 1H,
J=6.0, 18.6 Hz), 2.49 (dd, 1H,
J=4.8, 12.0 Hz), 2.47 (m, 4H), 2.32 (ddd, 1H,
J=3.0, 3.0, 14.4 Hz), 2.16 (ddd, 1 H,
J=4.2, 12.6, 12.6 Hz), 1.89 (ddd, 1 H,
J=3.0, 4.8, 13.2 Hz), 1.63 (ddd, 1 H,
J=3.0, 13.8, 13.8 Hz), 1.59 (dd, 1 H,
J=3.6, 13.2 Hz), 1.38 (t, 3H,
J=7.2 Hz);
13C NMR (CDCl
3, 150 MHz) δ 207.51, 152.89, 147.59, 133.08, 130.59, 130.22, 122.59, 119.43, 90.69,
70.20, 65.09, 64.40, 50.05, 45.06, 42.71, 36.02, 31.11, 30.56, 22.27, 14.15; MS (+El)
m/
z (%) 373 (100), 329 (21), 301 (99), 244 (34), 216 (38); HRMS (+EI) calcd for C
20H
23NO
6: 373.15254. Found 373.15284.
Example 5: Noroxymorphone
[0110]

[0111] A. Acetic acid buffer: The oxazolidine from Example 3 (0.1 g, 0.29 mmol) was suspended
in AcOH/NH
3 buffer (pH 9, 10% w/w, 1.5 mL) and heated for 16 hours at 50 °C. The reaction mixture
was then cooled to room temperature and stirred for an additional two hours. A light-brown
precipitate of product was filtered off and dried to yield 69 mg (82%) of noroxymorphone
as a brownish solid. m.p. >300 °C (lit >300°C).
xvi
[0112] B. Ammonium carbonate buffer: The oxazolidine from Example 3 (0.2 g, 0.57 mmol) was
suspended in NH
4HCO
3/NH
3 buffer (pH 9, 10% w/w, 1 mL) and heated for 16 hours at 50°C. The reaction mixture
was then cooled to room temperature and stirred for an additional two hours. The light
brown precipitate of product was filtered off and dried to yield 131 mg (78%) of noroxymorphone
as a brownish solid. m.p. >300 °C.
Example 6: Naltrexone
[0113]

[0114] Cyclopropylmethyl bromide (64 mg; 0.479 mmol) and Et
3N (45 µl; 0.327 mmol) were added to a suspension of noroxymorphone (Example 5, 100
mg; 0.348 mmol) in a mixture of N-Methyl-2-pyrrolidone (NMP)/H
2O (10:1; 0.35 mL). The reaction vessel was purged with argon and the reaction mixture
was stirred at 70 °C for 2h. At that time, additional Et
3N (45 µl; 0.327 mmol) was added and the mixture was stirred for an additional 6 h
at 70 °C. The reaction mixture was then cooled to room temperature, diluted with dichloromethane
(15 mL) and washed with saturated NaHCO
3 (3 x 3 mL). The aqueous layer was re-extracted with dichloromethane (5 mL) and the
combined organic layers were dried over MgSO
4. Column chromatography of the residue (dichloromethane/methanol 4:1) afforded 103
mg (87%) of naltrexone as a white solid: mp 173-175 °C (acetone), mp 159-161 °C (MeOH),
[lit. mp 174-176 °C (acetone)]
xvii identical in all respects to the material described in the literature.
xviii
[0115] R
f 0.42 (ethyl acetate + 20% MeOH); [α]
20D = -207.00 (c=1, CHCl
3); IR (CHCl
3) v 3568, 3359, 3010, 2931, 2834, 1723, 1620, 1317, 1146, 1058, 943;
1H NMR (600 MHz, CDCl
3) δ 6.74 (d,
J=8.1 Hz, 1 H), 6.60 (d,
J=8.1 Hz, 1 H), 5.82 (bs, 1 H, OH), 4.74 (s, 1 H), 3.21 (d,
J=5.9 Hz, 1H), 3.11-3.03 (m, 2H), 2.72 (dd,
J=12.0, 4.8 Hz, 1H), 2.58 (dd,
J=18.4, 6.0 Hz, 1H), 2.49-2.39 (m, 3H), 2.34 (ddd,
J=14.5, 3.0, 3.0 Hz, 1H), 2.18 (ddd,
J=12.2, 3.8, 3.8 Hz, 1H), 1.91 (m, 1H), 1.66 (ddd,
J=14.2, 14.2, 3.3 Hz, 1 H), 1.59 (ddd,
J=12.8, 2.7 Hz, 1 H), 0.88 (m, 1 H), 0.57 (m, 2H), 0.16 (m, 2H);
13C NMR (150 MHz, CDCl
3) δ 210.02, 142.51, 138.80, 129.05, 124.25, 119.90, 117.91, 90.60, 70.32, 62.01, 59.21,
51.07, 43.60, 36.21, 31.36, 30.65, 22.62, 9.42, 4.02, 3.81; MS (+El) m/z (%): 47 (15),
55 (41), 84 (100), 110 (12), 202 (5), 256 (12), 286 (7), 300 (15), 341 (64); HRMS
calcd for C
20H
23NO
4 341.1627, found 341.16320.
Example 7: Naloxone
[0116]

[0117] Allyl bromide (56 mg; 0.463 mmol) and Et
3N (45 µl; 0.327 mmol) were added to a suspension of noroxymorphone (Example 5, 100
mg; 0.348 mmol) in a mixture of NMP/H
2O (10:1; 0.35 mL). The reaction vessel was purged with argon and the mixture was stirred
at 70 °C for 2h. At that time, additional Et
3N (45 µl; 0.327 mmol) was added and the mixture was stirred for an additional 7.5
h at 70 °C. The reaction mixture was then cooled to room temperature, diluted with
dichloromethane (15 mL), and washed with saturated NaHCO
3 (3 x 3 mL). The aqueous layer was re-extracted with dichloromethane (5 mL) and the
combined organic layers were dried over MgSO
4. Column chromatography of the residue (dichloromethane/methanol 4:1) afforded 96
mg (84%) of naloxone as a white solid mp: 181-182 °C (ethyl acetate), [lit. mp 173-175]
xix [lit. 179.5 °C (toluene)]
xx identical in all respects to the material described in the literature.
xxi
Example 8: Nalbuphone
[0118]

[0119] A slurry of noroxymorphone (Example 5, 220 mg; 0.766 mmol), sodium hydrogen carbonate
(77 mg; 0.92 mmol), cyclobutylmethyl bromide (160 mg; 1.07 mmol) and NMP (1 mL) was
stirred under a nitrogen atmosphere at 90 °C for 19 h. Then the reaction mixture was
cooled and quenched with water (10 mL). After adjusting the pH to 9, the product was
extracted with DCM (3x5 mL). The combined organic layers were washed with water, brine
and dried over MgSO
4. Column chromatography afforded 180 mg (66%) of nalbuphone as a white solid; mp 170-172
°C (acetone), [lit. 173-174 °C (chloroform)]
xxii; R
f 0.64 (ethyl acetate + 20% methanol); [α]
20D = -180.44 (c =1.0, MeOH); IR (CHCl
3 v 3561, 3454, 2966, 2931, 2830, 1720, 1616, 1457, 1318, 1142, 1057, 944 cm
-1;
1H NMR (600 MHz, CDCl
3) δ 6.74 (d,
J=8.0 Hz, 1H), 6.61 (d,
J=8.0 Hz, 1H), 5.64 (bs, 1H, OH), 4.72 (s, 1H), 3.11 (d,
J=18.4 Hz, 1 H), 3.04 (ddd,
J=14.4, 14.4, 3.6 Hz, 1H), 2.92 (d,
J=4.9 Hz, 1H), 2.57 (m, 5H), 2.42 (ddd,
J=12.4, 12.4, 4.4 Hz, 1H), 2.33 (d,
J=14.4 Hz, 1H), 2.20 (ddd,
J=12.0, 12.0, 2.2 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 1H), 1.90 (m, 2H), 1.87 (m, 2H),
1.66 (ddd,
J=13.6, 13.6, 2.2 Hz, 1 H), 1.56 (d,
J=12.6 Hz, 1H);
13C NMR (150 MHz, CDCl
3) δ 209.68, 143.45, 138.69, 129.02, 124.34, 119.87, 117.71, 90.58, 70.31, 62.74, 60.48,
50.93, 43.74, 36.18, 33.73, 31.32, 30.69, 27.00, 26.79, 22.96, 18.76; MS (FAB+) m/z
(%): 41 (27), 69 (9), 98 (5), 300 (88), 355 (38), 356 (100); HRMS calcd for C
21H
26NO
4 356.1856, found 356.18552.
Example 9: (5aR,8aS, 11aR, 11bS)-6-Allyl-2-methoxy-11-oxo-5,5a,9,10,11-pentahydro-6, 11b-ethano-7H-furo[2',3',4',5':4,5]phenanthro[9,8a-d]oxazol-6-ium
bromide
[0120]

[0121] The compound from Example 2 (20 mg; 0.064 mmol) was dissolved in nitromethane (0.5
mL) and allyl bromide (77 mg; 0.63 mmol) was added. The reaction mixture was heated
to 85 °C, stirred for 16 hours and then cooled to room temperature. The precipitated
solid was filtered and dried in vacuo to yield essentially pure quarternary salt (22
mg, 80 %).
[0122] R
f= 0.10-0.15 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]
D20= - 108.4 (c 1, MeOH); IR (KBr, cm
-1) v 3416, 2960, 2933, 2839, 1729, 1638, 1615, 1508, 1446, 1331, 1319, 1278, 1194,
1165, 1112, 1087, 1061, 1007, 948, 916, 801;
1H NMR (CDCl
3, 300 MHz) δ 6.97 (d, 1 H,
J=8.4 Hz), 6.89 (d, 1 H,
J=8.4 Hz), 6.09 (m, 1 H), 5.83 (d, 1 H,
J=15.6 Hz), 5.78 (d, 1 H,
J=9.3 Hz), 5.50 (d, 1H,
J=5.1 Hz), 5.24 (dd, 1H,
J=2.1, 5.1 Hz), 5.12 (s, 1H), 4.41 (dd, 1H,
J=7.5, 13.2 Hz), 4.33 (d, 1 H,
J=7.5 Hz), 4.17 (dd, 1 H,
J=7.2, 13.2 Hz), 3.93 (s, 3H), 3.77 (m, 1 H), 3.72 (m, 1 H), 3.40 (dddd, 1 H,
J=3.3, 3.3, 7.2, 21.3 Hz), 3.24 (ddd, 1 H,
J=2.1, 4.8, 15.0 Hz), 2.99 (ddd, 1H,
J=4.2, 14.1, 14.1 Hz), 2.77 (ddd, 1H,
J=5.7, 14.4, 14.4 Hz), 2.39-2.30 (m, 2H), 1.95 (m, 1H), 1.78 (ddd, 1 H,
J=3.9, 15.6, 15.6 Hz);
13C NMR (CDCl
3, 150 MHz): Major rotamer δ 205.7, 144.8, 143.5, 128.5, 126.9, 124.0, 120.6, 120.3,
117.1, 89.4, 87.9, 83.7, 70.3, 60.6, 56.3, 51.7, 50.5, 34.4, 30.8, 29.4, 22.5; MS
(FAB+)
m/
z (%) 354 (100); HRMS (FAB+) calcd for C
21H
24NO
4: 354.17053. Found 354.17047.
[0123] Note: carbon signals at 600 MHz/150 MHz NMR indicate rotamers.
Example 10: (5aR,8aS,11aR,11bS)-2-Acetoxy-6-allyl-11-oxo-5,5a,9,10,11-pentahydro-6,11b-ethano-7H-furo[2',3',4',5':4,5Jphenanthro]9,8a-d]oxazol-6-ium
bromide
[0124]

[0125] The compound of Example 3 (25.5 mg, 0.075 mmol) was stirred with 3 eq allyl bromide
(19.0 µL, 0.224 mmol) in 0.3 mL nitromethane. After stirring for two hours, the solvents
were evaporated to yield 36 mg of the title compound in essentially quantitative yield.
[0126] R
F = 0.2 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]
D20 = -88 to -92 (c 1, MeOH); IR (KBr) ν 3448, 2931, 1761, 1731, 1554, 1448, 1198 cm
-1;
1H NMR(300MHz, MeOD)δ 7.06 (d, 1 H,
J = 8.4 Hz), 6.98 (d, 1 H,
J = 8.1 Hz), 6.21-6.06 (m, 1 H), 5.87 (d, 1 H,
J = 16.5 Hz), 5.78 (d, 1 H,
J = 9.9 Hz), 5.55 (d, 1 H,
J = 5.4 Hz), 5.31 (dd, 1 H,
J = 2.1, 5.4 Hz), 5.20 (s, 1 H), 4.54-4.46 (m, 2H), 4.29 (dd, 1 H,
J = 7.2, 13.2 Hz), 3.90 (d, 1 H,
J = 20.7 Hz), 3.80 (dd, 1 H,
J = 5.4, 13.2 Hz), 3.55-3.42 (m, 1 H), 3.27 (dddd,
J = 1.4, 4.4, 6.0, 12.7 Hz), 2.98 (ddd, 1 H,
J = 4.2, 14.1, 14.1 Hz), 2.81 (ddd, 1H,
J= 5.7, 13.5, 13.8 Hz), 2.39-2.30 (m, 2H), 2.32 (s, 3H), 2.00-1.91 (m, 1 H), 1.79 (ddd,
1 H,
J = 3.3, 14.4, 14.4 Hz) ppm;
13C NMR (75 MHz, MeOD) δ 205.4, 168.8, 147.7, 132.9, 128.7, 127.6, 126.4, 124.6, 124.1,
120.6, 89.9, 87.9, 83.5, 70.1, 60.6, 51.5, 50.5, 34.5, 30.8, 29.2, 23.0, 19.2 ppm;
MS (FAB+)
m/
z %: 414 (M+CH
3OH) (100), 382 (M
+) (83), 352 (13), 310 (7), 185 (6), 77 (7), 43 (11). HRMS Calcd for C
22H
24NO
5: 382.16545 found: 382.16100.
Example 11: (5aR,8aS,11aR,11bS)-6-Allyl-2-hydroxy-11-oxo-5,5a,9,10,11-pentahydro-6,11b-ethano-7H-furo[2',3',4',5':4,5]phenanthro[9,8a-d]oxazol-6-ium hydroxide
[0127]

[0128] The compound of Example 3 (60 mg, 0.176 mmol) was dissolved in nitromethane (0.6
mL) and allyl bromide (0.15 mL, 1.759 mmol) was added to the mixture. The solution
was stirred at room temperature for two hours, when TLC (DCM/MeOH/NH
4OH 90/9/1) indicated only the formation of the product. No precipitate was observed
at that time and the mixture was allowed to stir overnight. TLC after 12 hours was
identical with the one from the day before. Solvents were evaporated under a stream
of argon, and an NMR of the crude material was obtained. NMR showed 10% of "solvated"
product. After leaving the compound in CD
3OD for a few hours, the ratio of "naked" to "solvated" product changes (40%, see NMR
at 600 MHz). The CD
3OD was evaporated, the mixture was stirred in a saturated solution of NaHCO
3 (0.3 mL) and after concentration to dryness the residue was purified by chromatography
on silica gel (7 mL) in DCM/MeOH/H
2O 5/1/0.06) to furnish 52 mg (83%) of the title compound (as a zwitterion).
[0129] R
F = 0.1 (dichloromethane/methanol/ammonium hydroxide 90:8:2); [α]
D20 = - 106.971 (c 2, MeOH); IR (KBr) ν 3422, 3258, 2969, 1728, 1627, 1504, 1464, 1319,
1087, 920 cm
-1;
1H NMR (300 MHz, MeOD) δ 6.80 (s, 2H), 6.15-6.04 (m, 1H), 5.83 (d, 1 H,
J = 17.1 Hz), 5.78 (d, 1 H,
J = 9.9 Hz), 5.50 (d, 1 H,
J = 5.4 Hz), 5.25 (dd, 1 H,
J = 2.4, 5.4 Hz), 5.10 (s, 1 H), 4.42 (dd, 1H,
J = 7.5, 13.2 Hz), 4.34 (d, 1H,
J = 7.2 Hz), 4.19 (dd, 1H,
J = 6.9, 13.2 Hz), 3.78-6.68 (m, 2H), 3.36 (s, 1 H), 3.34-3.22 (m, 1H), 3.00 (ddd 1H,
J = 4.8,14.1,14.1 Hz), 2.77 (ddd, 1H,
J = 6.0, 13.5, 13.5 Hz), 2.40-2.29 (m, 2H), 2.00-1.91 (m, 1 H), 1.79 (ddd, 1 H,
J = 3.3, 15.6, 15.6 Hz) ppm;
13C NMR (75 MHz, CD
3OD) δ 206.6, 143.5, 140.3, 128.6, 126.6, 124.1, 120.6, 119.2, 118.8, 89.3, 87.9, 83.8,
70.4, 60.6, 51.7, 50.7, 34.5, 30.8, 29.4, 22.6 ppm; MS (FAB+) m/z %: 340 (M
+) (13), 176 (16), 149 (27), 136 (21), 95 (24), 83 (32), 69 (70), 55 (68), 43 (100).
HRMS Calcd for C
20H
22NO
4: 340.15488 found: 340.15459.
Example 12: 3-Acetoxy-17-(2-nitroethyl)-noroxymorphone
[0130]

[0131] The compound of Example 3 (59 mg, 0.173 mmol) was dissolved in nitromethane (0.6
mL) and cyclopropylmethyl bromide (50.0 µL, 0.519 mmol) was added to the mixture.
The solution was stirred at room temperature for 7 hours at which time TLC analysis
(DCM/MeOH/NH
4OH 90/9/1) indicated no progress and the mixture was heated at 50 °C overnight. After
this time, TLC analysis showed traces of starting material and additional cyclopropylmethyl
bromide (50.0 µL, 0.519 mmol, 3 equiv) was added. After 6 hours of stirring at room
temperature, the solvents were evaporated under a stream of argon. Chromatography
of the residue (6 mL of silica gel) in DCM/MeOH 100/1 gradient elution to 25/1 gave
as product, 27 mg of the titled compound (38%) as a colorless glassy material, in
addition to a inseparable mixture of compounds (14 mg). After trituration with MeOH,
the titled compound was obtained as a white crystalline solid.
[0132] R
F = 0.9 (dichloromethane/methanol/ammonium hydroxide 90:8:2); mp = 145-174 °C, becomes
brown (MeOH); [α]
D20 = -148.46 (c 1, CHCl
3); IR (KBr) ν 3427,2931, 2837,1767, 1728, 1554, 1443, 1370, 1214, 1187 cm
-1;
1H NMR (300 MHz, CDCl
3) δ 6.87 (d, 1H,
J = 8.1 Hz), 6.71 (d, 1 H,
J = 8.1 Hz), 4.69 (s, 1 H), 4.62-4.47 (m, 2H), 3.27 (ddd, 1 H,
J = 4.8, 8.1, 14.4 Hz), 3.11 (d, 1 H,
J = 18.9 Hz), 3.07 (dd, 1 H,
J = 4.2, 10.2 Hz), 3.01 (d, 1 H,
J = 6.3 Hz), 2.99 (dd, 1 H,
J = 5.1, 12.9 Hz), 2.77 (dd, 1H,
J = 5.7, 18.6 Hz), 2.66-2.59 (m, 1H), 2.42-2.26 (m, 2H), 2.33 (s, 3H), 1.90 (ddd, 1H,
J = 3.0, 5.1, 13.2 Hz), 1.67-1.55 (m, 2H) ppm;
13C NMR (75 MHz, CDCl
3) δ 207.4, 168.5, 147.8, 132.8, 129.8, 129.6, 123.2, 119.4, 90.4, 73.7, 70.1, 70.0,
63.9, 51.9, 50.2, 43.4, 35.9, 31.0, 30.3, 24.7, 20.8 ppm; MS (FAB+) m/z %: 403 (M+H
+) (100), 402 (M
+) (21), 385 (14), 360 (45), 342 (17), 300 (6), 214 (15), 187 (7), 129 (7), 84 (7),
56 (14), 43 (19). HRMS Calc'd for C
20H
23N
2O
7: 403.15053 found: 403.15129.
Example 13:
[0133]

[0134] In preliminary experiments, the reduction of the above quaternary salt was attempted
under a variety of conditions, including the activation of the C-14 oxygen with Lewis
acids. The C-14 methyl ether was obtained as shown in the above scheme. Hydrolysis
of the compound under acid buffer or basic conditions provided naltrexone.
[0135] While the present application has been described with reference to what are presently
considered to be the preferred examples, it is to be understood that the application
is not limited to the disclosed examples. To the contrary, the application is intended
to cover various modifications and equivalent arrangements included within the spirit
and scope of the appended claims.
[0136] All publications, patents and patent applications are herein incorporated by reference
in their entirety to the same extent as if each individual publication, patent or
patent application was specifically and individually indicated to be incorporated
by reference in its entirety. Where a term in the present application is found to
be defined differently in a document incorporated herein by reference, the definition
provided herein is to serve as the definition for the term.
FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE SPECIFICATION
[0137]
- i von Braun, J.; Chem. Ber., 1900, 33, 1438.
- ii Cooley, J.H.; Evain, E.J.; Synthesis 1989, 1.
- iii Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T. J. Org. Chem.
1984, 49, 2081.
- iv (a) K. M. Madyastha, Proc. Indian Acad. Sci. 1994, 106, 1203; (b) K. M. Madyastha, G. V. B. Reddy, J. Chem. Soc. Perkin Trans. 1 1994, 911.
- v Chaudhary, V; Leisch, H.; Moudra, A.; Allen, B.; De Luca, V.; Cox, D. P.; Hudlicky,
T. Collect. Czech. Chem. Commun. 2009, 74, 1179-1193.
- via (a) G. Kok, T. D. Asten, P. J. Scammells, Adv. Synth. Catal. 2009, 351, 283; (b) Z. Dong, P. J. Scammells, J. Org. Chem. 2007, 72, 9881.
- vii Smith, C.; Purcell, S.; Waddell, L.; Hayes, N.; Ritchie, J.; WO 2005/028483.
- viii Rinner, U.; Adams, D. R.; dos Santos, M. L.; Hudlicky, T. Synlett 2003, 1247-1252.
- ix (a) Nicolaou, K. C.; Snyder, S. A.; Nalbandian, A. Z.; Longbottom, D. A. J. Am. Chem.
Soc. 2004, 126, 6234; (b) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V. Angew.
Chem. Int. Ed. Engl. 2002, 41, 834; (c) Nicolaou, K. C.; Longbottom, D. A.; Snyder, S. A.; Nalbandian, A. Z.; Huang, X. Angew.
Chem. Int. Ed. Engl. 2002, 41, 3866.
- x Banfield, S. C.; Omori, A. T.; Leisch, H.; Hudlicky, T. J. Org. Chem. 2007, 72, 4989-4992.
- xi (a) For a recent summary of new applications of the Burgess reagent see: Leisch, H.; Sullivan, B.; Fonovic, B.; Dudding, T.; Hudlicky, T. Eur. J. Org. Chem.
2009, 2806-2819; Reviews of applications of the Burgess reagent: (b) Santra, S. Synlett 2009, 852; (c) Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Huang, X. Chem.
Eur. J. 2004, 10, 5581; (d) Khapli, S.; Dey, S.; Mal, D. J. Ind. Inst. Sci. 2001, 81, 461; (e) Burckhardt, S. Synlett 2000, 559; (f) Lamberth, C. J. Prakt. Chem. 2000, 342, 518; (g) Taibe, P.; Mobashery, S. in Encyclopedia of Reagents in Organic Synthesis, vol. 5,
Paquette, L. A., Ed., Wiley, Chichester, 1995, p. 3345.
- xii Metcalf, T. A.; Simionescu, R.; Hudlicky, T. J. Org. Chem. 2010, 75, 3447-3450.
- xiii Leisch, H.; Saxon, R.; Sullivan, B.; Hudlicky, T. Synlett 2006, 445-449.
- xiv Use of the Burgess reagent in natural product synthesis: a) cedrene: Rigby, J. H.; Kirova-Snover, M. Tetrahedron Lett. 1997, 38, 8153; b) narciclasine: Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655; c) taxol: Holton, R. A.; Kim, H. B.; Sonoza, C.; Liang, F.; Biediger, R. J.; Boatman, P. D.;
Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang,
S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116,
1599; d) efrotomycin: Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691; e) pravastatin: Daniewski, A. R.; Wovkulich, P. M.; Uskokovic, M. R. J. Org. Chem. 1992, 57, 7133; f) balanol: Sullivan, B.; Gilmet, J.; Leisch, H.; Hudlicky, T. J. Nat. Prod. 2008, 71, 346-350.
- xv Edward M. Burgess, Harold R. Penton Jr., and E. A. Taylor. "Thermal reactions of alkyl
N-carbomethoxysulfamate esters". J. Org. Chem. 1973, 38(1):26-31.
- xvi Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe, J. Tetrahedron Lett. 1977, 18, 1567.
- xvii (a) Pillai, O.; Hamad, M.O.; Crooks, P.A.; Stinchcomb, A.L. Pharm. Res., 2004, 21, 1146; (b) Hamad, M.O.; Kiptoo, P.K.; Stinchcomb, A.L.; Crooks, P.A.; Bioorg. Med. Chem. 2006,
14, 7051.
- xviii Naltrexone mp reference: Olofson et al. US Pat. No. 4,141,897 (1976).
- xix Ukrainets, I.V.; Tkach, A.A.; Gorokhova, O.V.; Turov, A.V.; Linsky, I.V.; in Chemistry
of Heterocyclic Compounds (New York, NY, United States), 2009, vol. 45, #4, p. 405.
- xxAndre, J.; Dormoy, J.; Haymes, A. Synth. Comm., 1992, 22, 2313.
- xxi (a) Lewenstein et al. US Pat. No. 3,254,088 (1966); (b) Sankyo, Belg. Pat. No. 615,009 (1962).
- xxii Research Corp. Patent: US 4,161,597, 1979; Chem. Abstr. vol. 92, #22671.
FURTHER EMBODIMENTS OF THE INVENTION
[0138]
- 1. A process for the preparation of a compound of Formula I:

wherein
- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-ioalkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when -O represents =O, then R2 is not present; and
PG is a protecting group,
the process comprising:
- (a) reacting a compound of Formula II with an oxidizing agent under conditions to
provide a compound of Formula III:

wherein
- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-ioalkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when -O represents =O, then R2 is not present; and
PG is a protecting group; and
- (b) reacting the compound of Formula III with a cyclodehydration reagent under conditions
to provide the compound of Formula I,
wherein in the compounds of Formulae I, II and III, one or more available hydrogens
in R1 and R2 is/are optionally replaced with F and/or one or more of available atoms in R1 and R2 is/are optionally replaced with an isotopic label.
- 2. The process of embodiment 1, wherein the compound of Formula I is selected from
a compound of Formula l(a), l(b) and l(c):

wherein
---- represents a single or double bond;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-ioalkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, and PG is a protecting group; and one or more available hydrogens
in R1 and R2 is/are optionally replaced with F and/or one or more of available atoms in R1 and R2 is/are optionally replaced with an isotopic label.
- 3. The process of embodiment 1 or 2, wherein R1 and R2 are independently selected from C1-6alkyl, phenyl, naphthyl, indanyl, C3-6cycloalkyl, C1-6alkyleneC6-10aryl, C1-6alkyleneC3-6cycloalkyl and PG.
- 4. The process of embodiment 3, wherein R1 and R2 are independently selected from Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG.
- 5. The process of any one of embodiments 1 to 4, wherein the oxidizing agent is a
peroxide or a peracid.
- 6. The process of embodiment 5, wherein the oxidizing agent is m-chloroperbenzoic
acid (mCPBA).
- 7. The process of any one of embodiments 1 to 6, wherein the cyclodehydration reagent
is selected from Burgess reagent, TsCl, CrO3, DCC, XtalFluor™ and carbonyldiimidazole, preferably Burgess reagent.
- 8. The process of embodiment 7, wherein the conditions to provide the compounds of
Formula I from the compounds of Formula III using Burgess reagent comprise a temperature
of about -50 °C to about 50 °C, in an inert organic solvent or mixture of organic
solvents for a time for the conversion of the compound of Formula III to the compound
of Formula I to proceed to a sufficient extent.
- 9. The process of embodiment 8, wherein the Burgess reagent and the compound of Formula
III are used in a molar ratio of about 1.5:1 to about 1:1.
- 10. A process for preparing compounds of Formula V:

wherein
- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present;
PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl; and
X is a counteranion, comprising
reacting a compound of Formula I as defined in any one of embodiments 1 to 4:
with an alkylating reagent of Formula VI:
R3-LG VI,
wherein R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl and LG is a leaving group,
under conditions to provide the compound of Formula V,
wherein in the compounds of Formulae I, V and VI, one or more available hydrogens
in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label.
- 11. The process of embodiment 10, wherein R3 is selected from C1-6alkyl, C2-6alkenyl, phenyl, naphthyl, indanyl, C3-6cycloalkyl, C3-6cycloalkenyl, C1-6alkyleneC6-10aryl, and C1-6alkyleneC3-6cycloalkyl.
- 12. The process of embodiment 11, wherein R3 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
- 13. The process of any one of embodiments 10 to 12, wherein LG is selected from halo,
Ms, Ts, Ns, Tf and C1-6acyl.
- 14. The process of any one of embodiments 10 to 13, wherein X is the anion of LG.
- 15. The process of any one of embodiments 10 to 14, wherein the compound of Formula
V is selected from a compound of Formula V(a), V(b) and V(c):

wherein
---- represents a single or double bond; and
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-ioalkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, and PG is a protecting group; R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion, and
one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label.
- 16. A process for preparing compounds of Formula VII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other and when - -O represents =O,then H is not present;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion; and
one or more available hydrogens in R3 is/are optionally replaced with F and/or one or more of available atoms in R3 is/are optionally replaced with an isotopic label,
the process comprising deprotecting the compounds of Formula V as defined in any one
of embodiments 10 to 15, wherein R1 and/or R2 are PG.
- 17. A process for preparing compounds of Formula VIII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R4 and R5 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R5 is not present, or
R4 and R5 are H if, in the compounds of Formula V, R1 and R2 are a PG that is removed under the reducing conditions;
PG is a protecting group that is not removed under the reducing conditions, and
one or more available hydrogens in R3, R4 and R5 is/are optionally replaced with F and/or one or more of available atoms in R3, R4 and R5 is/are optionally replaced with an isotopic label,
the process comprising treating compounds of Formula V as defined in any one of embodiments
10 to 15 under reducing conditions.
- 18. A process for preparing compounds of Formula IX:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R6 and R7 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R7 is not present, or
R6 and R7 are H if, in the compounds of Formula V, R1 and R2 are a PG that is removed under the hydrolysis conditions;
PG is a protecting group that is not removed under the hydrolysis conditions, and
one or more available hydrogens in R3, R6 and R7 is/are optionally replaced with F and/or one or more of available atoms in R3, R6 and R7 is/are optionally replaced with an isotopic label,
the process comprising treating compounds of Formula V as defined in any one of embodiments
10 to 15 under hydrolysis conditions.
- 19. The process of embodiment 17, wherein the reducing conditions to provide the compounds
of Formula VIII comprise treating the compounds of Formula V with a suitable reducing
agent, such as metal hydride reducing agents, optionally in the presence of a Lewis
acid, for a time and temperature for the conversion of the compound of Formula V to
the compound of Formula VIII to proceed to a sufficient extent.
- 20. The process of embodiment 18, wherein the hydrolysis conditions to provide the
compounds of Formula IX comprise treating the compounds of Formula V under suitable
acidic (for example acetic acid/ammonia buffer) or basic (for example ammonium bicarbonate/ammonia)
conditions for a time and temperature for the conversion of the compound of Formula
V to the compound of Formula IX to proceed to a sufficient extent.
- 21. A process for preparing compounds of Formula X:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R8 and R9 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R9 is not present; or
R8 and R9 are H, if in the compound of Formula I, R1 and R2 are a PG that is removed under the hydrolysis conditions; and
PG is a protecting group,
wherein in the compounds of Formula X, one or more available hydrogens in R8 and R9 is/are optionally replaced with F and/or one or more of available atoms in R8 and R9 is/are optionally replaced with an isotopic label,
the process comprising treating the compounds of Formula I as defined in any one of
embodiments 1 to 9 under either acidic or basic conditions.
- 22. The process of embodiment 21, wherein PG in the compounds of Formula I is a protecting
group that is removed under conditions to hydrolyze the compound of Formula I to the
compound of Formula X.
- 23. The process of embodiment 21, wherein PG is a protecting group that is not removed
under conditions to hydrolyze the compound of Formula I to the compound of Formula
X and is optionally removed in a separate step after the preparation of the compound
of Formula X.
- 24. A process for preparing compounds of Formula XII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R8 and R9 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R9 is not present;
PG is a protecting group;
R10 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl; and
one or more available hydrogens in R8, R9 and R10 is/are optionally replaced with F and/or one or more of available atoms in R8, R9 and R10 is/are optionally replaced with an isotopic label,
the process comprising selectively alkylating the N-17 of the compounds of Formula
X as defined in any one of embodiments 21-23 by reaction with a compound of the Formula
R10-LG1 (XI), wherein LG1 is a leaving group and R10 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl under alkylation conditions.
- 25. The process of embodiment 24, wherein R8 and/or R9 in the compounds of Formula XII is PG, and the compounds of Formula XII are further
treated under conditions to remove the PG to provide the corresponding compounds of
Formula XII wherein R8 and/or R9 are H.
- 26. A compound of Formula V:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R2 is not present;
PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion, and
one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label,
or a salt or solvate thereof.
- 27. The compound of embodiment 26, wherein R1 and R2 are independently selected from C1-6alkyl, phenyl, naphthyl, indanyl, C3-6cycloalkyl, C1-6alkyleneC6-10aryl, C1-6alkyleneC3-6cycloalkyl and PG.
- 28. The compound of embodiment 27, wherein R1 and R2 are independently selected from Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG.
- 29. The compound of any one of embodiments 26 to 28, wherein R3 is selected from C1-6alkyl, C2-6alkenyl, phenyl, naphthyl, indanyl, C3-6cycloalkyl, C3-6cycloalkenyl, C1-6alkyleneC6-10aryl, and C1-6alkyleneC3-6cycloalkyl.
- 30. The compound of embodiment 29, wherein R3 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
- 31. The compound of any one of embodiments 26 to 30, wherein X is OH-, Br or Cl-.
- 32. The compound of embodiment 26, selected from a compound of Formula V(a), V(b)
and V(c):

wherein
---- represents a single or double bond; and
R1 and R2 are independently selected from C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, and PG is a protecting group;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion, and
one or more available hydrogens in R1, R2 and R3 is/are optionally replaced with F and/or one or more of available atoms in R1, R2 and R3 is/are optionally replaced with an isotopic label,
or a salt or solvate thereof.
- 33. A compound of Formula VII: 1:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other and when - -O represents =O, then H is not present;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion; and
one or more available hydrogens in R3 is/are optionally replaced with F and/or one or more of available atoms in R3 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
- 34. The compound of embodiment 33, wherein R3 is selected from C1-6alkyl, C2-6alkenyl, phenyl, naphthyl, indanyl, C3-6cycloalkyl, C3-6cycloalkenyl, C1-6alkyleneC6-10aryl, and C1-6alkyleneC3-6cycloalkyl.
- 35. The compound of embodiment 34, wherein R3 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
- 36. The compound of any one of embodiments 33 to 35, wherein X is OH-, Br or Cl-.
- 37. The compound of embodiment 33, selected from a compound of Formula VII(a), VII(b)
and VII(c):

wherein
---- represents a single or double bond;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
X is a counteranion; and
one or more available hydrogens in R3 is/are optionally replaced with F and/or one or more of available atoms in R3 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
- 38. A compound of Formula VIII:

wherein
---- represents a single or double bond, provided that two double bonds are not adjacent
to each other;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R4 and R5 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when - -O represents =O, then R5 is not present;
PG is a protecting group; and
one or more available hydrogens in R3, R4 and R5 is/are optionally replaced with F and/or one or more of available atoms in R3, R4 and R5 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.
- 39. The compound of embodiment 38, wherein R3 is selected from C1-6alkyl, C2-6alkenyl, phenyl, naphthyl, indanyl, C3-6cycloalkyl, C3-6cycloalkenyl, C1-6alkyleneC6-10aryl, and C1-6alkyleneC3-6cycloalkyl.
- 40. The compound of embodiment 39, wherein R3 is selected from Me, Et, allyl, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
- 41. The compound of any one of embodiments 38 to 40, wherein R4 and R5 are independently selected from H, C1-6alkyl, phenyl, naphthyl, indanyl, C3-6cycloalkyl, C1-6alkyleneC6-10aryl, C1-6alkyleneC3-6cycloalkyl and PG.
- 42. The compound of embodiment 41, wherein R4 and R5 are independently selected from H, Me, Et, Ph, cyclobutyl, cyclopentyl, cyclohexyl,
Bn, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and PG.
- 43. The compound of embodiment 38, selected from a compound of Formula VIII(a), VIII(b)
and VIII(c):

wherein
---- represents a single or double bond;
R3 is selected from C3-10cycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl, C1-10alkyleneC6-10aryl and C1-10alkyleneC3-10cycloalkyl;
R4 and R5 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG;
PG is a protecting group; and
one or more available hydrogens in R3, R4 and R5 is/are optionally replaced with F and/or one or more of available atoms in R3, R4 and R5 is/are optionally replaced with an isotopic label, or
a salt or solvate thereof.